Project Summary Understanding the molecular pathways involved in the formation of aortic aneurysms and dissection has remained a challenge in the field of vascular biology. The LDL receptor-related protein (LRP1) is an endocytic signaling receptor that is widely expressed and regulates numerous intracellular processes. LRP1 has been identified as a susceptibility locus for abdominal aortic aneurysm9, thoracic aortic aneurysm and dissection10, hyperlipidemia11, and coronary artery disease12. Selective deletion of LRP1 in vSMC (smLRP1-/- mice) reveals that LRP1 protects against aortic aneurysm formation16?18. smLRP1-/- mice spontaneously develop aortic aneurysms and exhibit fragmentation of the elastic lamina and medial thickening, similar to that seen in aneurysmal aortic tissue from humans. Interestingly, aneurysm formation is not restricted to the aorta and occurs in other vascular beds, particularly the SMA17,18. Our Preliminary Data reveal a significant excess of TGF-? signaling in the SMA in smLRP1-/- mice, which we hypothesize drives the phenotype in these mice. Furthermore, common carotid artery ligation, which is used as a model for the study of vascular remodeling, is associated with significant remodeling in the SMA of smLRP1-/- mice but not wild type mice. Interestingly, administration of the angiotensin II type-1 (AT1 receptor antagonist, losartan almost completely reverses these changes. The overall goal of this proposal is to use a mouse model to identify the molecular mechanisms by which LRP1 protects the vasculature. We will use immunofluorescence studies to probe the vessel wall for evidence of phospho-SMAD2/3 and ERK 1/2, product of TGF-? and AngII signaling, respectively. In addition, we will employ inhibitors of the TGF-? signaling pathway to examine the role of this pathway. Finally, we will examine the effects of the AT1 receptor antagonist, losartan in comparison to the ?-blocker atenolol to further elucidate if the remarkable attenuation of remodeling is due to hemodynamic changes or rather, a modulation of AngII-mediated signaling in smLRP1-/- mice. Hypothesis: LRP1 is central to the development and maintenance of the vasculature. We hypothesize that LRP1 regulates vascular homeostasis by attenuating TGF-? and AngII-mediated signaling. Aim 1: Define the mechanisms by which LRP1 mediates mesenteric wall homeostasis. Aim 2: Determine the mechanisms by which LRP1 attenuates vascular remodeling in the SMA during physiologic stress.